Kallmann syndrome: symptoms, diagnosis, treatment and fertility

MedlinePlus says that at puberty most affected people do not develop secondary sex characteristics, such as facial hair growth and voice deepening in males, the start of monthly periods and breast development in females, and a growth spurt in both sexes. The NORD report says people typically come to attention in adolescence because of the delay in the physical changes of puberty.

MedlinePlus adds that males born with hypogonadotropic hypogonadism often have an unusually small penis (micropenis) and undescended testes. NORD notes the diagnosis can sometimes be made in infancy for this reason.

Not everyone has the same additional features. MedlinePlus lists failure of one kidney to develop, abnormalities of the bones of the fingers or toes, cleft lip with or without cleft palate, abnormal eye movements, hearing loss and tooth abnormalities. Some people have bimanual synkinesis, where the movements of one hand are mirrored by the other.

• Delayed or absent puberty.

• Reduced or absent sense of smell.

• Small penis and undescended testes in some males.

• Without treatment, infertility in most affected men and women.

• Sometimes: one kidney missing, short fingers or toes, cleft lip or palate, hearing loss, eye movement problems, mirror movements of the hands.

NORD describes Kallmann syndrome as a rare genetic disorder defined by delay or absence of the signs of puberty together with an absent or impaired sense of smell. It is due to an isolated deficiency of gonadotropin-releasing hormone (GnRH), the key hormone that starts reproductive development.

The hormone-making nerve cells normally start in the developing nose and travel into the brain alongside the nerves for smell. MedlinePlus says changes in the genes involved disrupt that journey, which is why both smell and puberty are affected. Without GnRH, the pituitary gland does not release LH and FSH, and the testes or ovaries are not switched on.

NORD names a closely related condition, normosmic idiopathic hypogonadotropic hypogonadism, in which puberty fails but the sense of smell is normal.

NORD says the diagnosis is typically made by a paediatric or adult endocrinologist. After a clinical examination, blood tests and imaging are used to confirm it. NORD says LH and FSH levels can be low or normal, which is inappropriate when testosterone or oestradiol is low, and an MRI scan of the hypothalamus and pituitary region is used to rule out structural abnormalities. The NORD report says the MRI may also show that the smell structures are absent.

Because it is genetic, testing for the genes involved may also help with diagnosis, according to NORD.

NORD says that first, hormone replacement therapy is used to induce secondary sexual characteristics: testosterone in males, and oestrogen and progesterone in females. It also says that once puberty has matured, those who wish to be fertile can be treated with injections of the pituitary hormones LH and FSH, or in some cases with GnRH itself, to make the testes produce sperm or the ovaries produce eggs.

NORD describes bone health as an issue to monitor: depending on the timing of puberty, the duration of hypogonadism and bone mineral density measurement, specific treatment for reduced bone mass should be considered.

The condition is usually lifelong. NORD says about 10 to 15 percent of patients may experience a recovery of their hormonal system, for reasons that are not clear.

MedlinePlus says that without treatment most affected men and women are unable to have biological children. NORD explains that treatment with gonadotropin injections or GnRH can induce the testes to make sperm or the ovaries to produce eggs once puberty has been achieved.

NORD also notes that in most people with this type of hormone deficiency who have no history of undescended testes, sperm function is usually normal and conception can occur even with relatively low sperm counts. Fertility treatment is a specialist decision, taken with the endocrinology team and, where needed, a fertility service. The NHS describes the general infertility pathway on its infertility page.

MedlinePlus says changes in more than 20 genes have been associated with it, most commonly ANOS1, CHD7, FGF8, FGFR1, PROK2 and PROKR2. Together, known gene changes account for about 30 percent of cases, and in the others the cause is unknown.

The inheritance pattern depends on the gene. MedlinePlus says changes in ANOS1 are X-linked recessive, passed most often through mothers who carry one altered copy. Changes in other genes often follow an autosomal dominant pattern, and in several families an autosomal recessive pattern has been seen. Some cases are new gene changes with no family history. NORD notes that genetic testing may help with diagnosis.

On the NHS, delayed puberty or lack of smell is usually first raised with a GP, who can refer to a paediatric or adult endocrinology service. Diagnosis and long-term hormone treatment sit with endocrinologists.

Private endocrinology consultations are also available, often with faster access to hormone tests and MRI. Hormone replacement and fertility treatment are long-term and should be supervised by a specialist team, whichever route you use.